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      Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome

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          Abstract

          Introduction

          A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed.

          Methods

          We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).

          Results

          Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.

          Conclusion

          Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.

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          Post-acute COVID-19 syndrome

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
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            Persistent Symptoms in Patients After Acute COVID-19

            This case series describes COVID-19 symptoms persisting a mean of 60 days after onset among Italian patients previously discharged from COVID-19 hospitalization.
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              MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights

              Since its first release over a decade ago, the MetaboAnalyst web-based platform has become widely used for comprehensive metabolomics data analysis and interpretation. Here we introduce MetaboAnalyst version 5.0, aiming to narrow the gap from raw data to functional insights for global metabolomics based on high-resolution mass spectrometry (HRMS). Three modules have been developed to help achieve this goal, including: (i) a LC–MS Spectra Processing module which offers an easy-to-use pipeline that can perform automated parameter optimization and resumable analysis to significantly lower the barriers to LC-MS1 spectra processing; (ii) a Functional Analysis module which expands the previous MS Peaks to Pathways module to allow users to intuitively select any peak groups of interest and evaluate their enrichment of potential functions as defined by metabolic pathways and metabolite sets; (iii) a Functional Meta-Analysis module to combine multiple global metabolomics datasets obtained under complementary conditions or from similar studies to arrive at comprehensive functional insights. There are many other new functions including weighted joint-pathway analysis, data-driven network analysis, batch effect correction, merging technical replicates, improved compound name matching, etc. The web interface, graphics and underlying codebase have also been refactored to improve performance and user experience. At the end of an analysis session, users can now easily switch to other compatible modules for a more streamlined data analysis. MetaboAnalyst 5.0 is freely available at https://www.metaboanalyst.ca . Graphical Abstract From raw data to statistical and functional insights using MetaboAnalyst 5.0.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2583914Role: Role: Role: Role: Role: Role: Role: Role:
                Role: Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/707896Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1039519Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1339214Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1176714Role: Role:
                URI : https://loop.frontiersin.org/people/707992Role: Role: Role:
                URI : https://loop.frontiersin.org/people/165385Role: Role: Role: Role: Role: Role: Role:
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                18 January 2024
                2024
                : 15
                : 1341843
                Affiliations
                [1] 1 School of Dentistry, Division of Foundational Sciences , Edmonton, AB, Canada
                [2] 2 The Metabolomics Innovation Centre, University of Alberta , Edmonton, AB, Canada
                [3] 3 Department of Medicine, Division of Rheumatology , Edmonton, AB, Canada
                [4] 4 Department of Chemistry, University of Alberta , Edmonton, AB, Canada
                [5] 5 Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, AB, Canada
                Author notes

                Edited by: Ahmed Yaqinuddin, Alfaisal University, Saudi Arabia

                Reviewed by: Suresh D. Sharma, United States Department of Health and Human Services, United States

                Cecilia Söderberg-Nauclér, Karolinska Institutet (KI), Sweden

                *Correspondence: Shokrollah Elahi, elahi@ 123456ualberta.ca

                †ORCID: Shokrollah Elahi, orcid.org/0000-0002-7215-2009

                Article
                10.3389/fimmu.2024.1341843
                10830702
                38304426
                52841fff-4768-4532-af43-2d1f8b4c6e1b
                Copyright © 2024 Saito, Shahbaz, Luo, Osman, Redmond, Cohen Tervaert, Li and Elahi

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 November 2023
                : 04 January 2024
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 85, Pages: 16, Words: 6587
                Funding
                Funded by: Canadian Institutes of Health Research , doi 10.13039/501100000024;
                Award ID: 174901
                Funded by: Arthritis Society , doi 10.13039/501100000142;
                Award ID: 00049
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. MO is supported by the Arthritis Society through a STAR/IMHA award (award 00049). DR and JC are supported by the Dutch Kidney Foundation. This work was primarily supported by a grant from the Canadian Institutes of Health Research (CIHR) and another grant from the Li Ka Shing Institute of Virology (both to SE).
                Categories
                Immunology
                Original Research
                Custom metadata
                Viral Immunology

                Immunology
                sarcosine,serine,soluble cd14,depression,cognitive performance
                Immunology
                sarcosine, serine, soluble cd14, depression, cognitive performance

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